The immunosuppressive drug cyclosporin A (CsA) is an undecapeptide fungal product which has a highly specific inhibitory effect on T cell activation or differentiation in vivo and in vitro. While CsA is currently widely used to prevent allograft rejection, its utility as a therapeutic agent is also being explored in a variety of autoimmune and neoplastic conditions. The discovery and purification (Handschumacher, 1984) and ultimately the cloning of the gene encoding the most abundant intracellular receptor for CsA, cyclophilin (Haendler, 1987), promised to shed light on the mechanism of T cell inhibition by CsA.
The subsequent discovery that cyclophilin possessed an intrinsic enzymatic activity, peptidylprolyl isomerase (PPIase)(Fischer, 1989; Takahashi, 1989), and that this enzymatic activity was blocked by CsA, provided the outline for a possible explanation for the immunosuppressive action of CsA. This approach was supported by results from another immunosuppressive drug-receptor system when the receptor for FK506, the FK binding protein (FKBP), was found also to possess PPIase activity (Harding, 1989; Siekierka, 1989) that was inhibited by FK506 (see U.S. Ser. No. 07/740,175, filed 5 Aug. 1991, (now abandoned) incorporated herein by reference). However, this proposal suffered on two counts: (1) cyclophilin is expressed ubiquitously, but its main actions in vivo are highly tissue restricted; and (2) CsA congeners reveal a dissociation between inhibition of PPIase activity and immunosuppressive potency (Sigal, 1991).